cis-5'-O-[4-(3-fluorophenyl)-2-oxo-1,2,3-dioxaphosphorin-2-yl]-2',3'-O-carbonyl-2'-C-methyladenosine | 926654-64-0

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷酸
• 英文名称: cis-5'-O-[4-(3-fluorophenyl)-2-oxo-1,2,3-dioxaphosphorin-2-yl]-2',3'-O-carbonyl-2'-C-methyladenosine
• 英文别名: (3aR,4R,6R,6aR)-4-(6-aminopurin-9-yl)-6-[[4-(3-fluorophenyl)-2-oxo-1,3,2lambda5-dioxaphosphinan-2-yl]oxymethyl]-3a-methyl-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-2-one；(3aR,4R,6R,6aR)-4-(6-aminopurin-9-yl)-6-[[4-(3-fluorophenyl)-2-oxo-1,3,2λ5-dioxaphosphinan-2-yl]oxymethyl]-3a-methyl-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-2-one
• CAS: 926654-64-0
• 化学式: C₂₁H₂₁FN₅O₈P
• 分子量: 521.399
• InChiKey: LOXJWTHQCVOGAD-JMAQBCBNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  36
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  159
• 氢给体数：
  1
• 氢受体数：
  13

反应信息

• 作为产物：
  描述：

  9-[(3aR,4R,6R,6aR)-6-[[4-(3-fluorophenyl)-2-oxo-1,3,2lambda5-dioxaphosphinan-2-yl]oxymethyl]-2,2,3a-trimethyl-6,6a-dihydro-4H-furo[3,4-d][1,3]dioxol-4-yl]purin-6-amine 以 水 、 N,N-二甲基甲酰胺 为溶剂， 生成 cis-5'-O-[4-(3-fluorophenyl)-2-oxo-1,2,3-dioxaphosphorin-2-yl]-2',3'-O-carbonyl-2'-C-methyladenosine
  参考文献：
  名称：

  Liver-Targeted Prodrugs of 2‘-C-Methyladenosine for Therapy of Hepatitis C Virus Infection

  摘要：

  2'-C-Methyladenosine exhibits impressive inhibitory activity in the cell-based hepatitis C virus (HCV) subgenomic replicon assay, by virtue of intracellular conversion to the corresponding nucleoside triphosphate (NTP) and inhibition of NS5B RNA-dependent RNA polymerase (RdRp). However, rapid degradation by adenosine deaminase (ADA) limits its overall therapeutic potential. To reduce ADA-mediated deamination, we prepared cyclic 1-aryl-1,3-propanyl prodrugs of the corresponding nucleoside monophosphate (NMP), anticipating cytochrome P450 3A-mediated oxidative cleavage to the NMP in hepatocytes. Lead compounds identified in a primary rat hepatocyte screen were shown to result in liver levels of NTP predictive of efficacy after intravenous dosing to rats. The oral bioavailability of the initial lead was below 5%; therefore, additional analogues were synthesized and screened for liver NTP levels after oral administration to rats. Addition of a 2',3'-carbonate prodrug moiety proved to be a successful strategy, and the 1-(4-pyridyl)-1,3-propanyl prodrug containing a 2',3'-carbonate moiety displayed oral bioavailability of 39%.

  DOI：

  10.1021/jm0701021

文献信息

• Novel 2'-c-methyl and 4'c-methyl nucleoside derivatives
  申请人：Erion Mark D.

  公开号：US20090118223A1

  公开（公告）日：2009-05-07

  Novel 2′-C-methyl nucleoside 5′-monophosphate and 4′-C-methyl nucleoside 5′-monophosphate derivatives, stereoisomers, and pharmaceutically acceptable salts or prodrugs thereof, their preparation, and their uses for the treatment of hepatitis C viral infection are described.